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WO2001021167A1 - Traitement des symptomes des voies urinaires basses, et compositions pharmaceutiques a utiliser dans le cadre dudit traitement - Google Patents

Traitement des symptomes des voies urinaires basses, et compositions pharmaceutiques a utiliser dans le cadre dudit traitement Download PDF

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Publication number
WO2001021167A1
WO2001021167A1 PCT/US2000/025534 US0025534W WO0121167A1 WO 2001021167 A1 WO2001021167 A1 WO 2001021167A1 US 0025534 W US0025534 W US 0025534W WO 0121167 A1 WO0121167 A1 WO 0121167A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor antagonist
pharmaceutically acceptable
muscaπnic
effective amount
reductase inhibitor
Prior art date
Application number
PCT/US2000/025534
Other languages
English (en)
Other versions
WO2001021167A8 (fr
Inventor
Elizabeth Stoner
Paul J. Drake
Mark A. Bach
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU77037/00A priority Critical patent/AU7703700A/en
Publication of WO2001021167A1 publication Critical patent/WO2001021167A1/fr
Publication of WO2001021167A8 publication Critical patent/WO2001021167A8/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Definitions

  • Lower Urinary Tract Symptoms is a well-recognized condition of men which includes some or all of the following: obstructive urinary symptoms such as slow u ⁇ nation; dribbling at the end of a urination; inability to urinate and/or the need to strain to urinate at an acceptable rate or irritative symptoms such as frequency and or urgency. These irritative symptoms may result from detrusor overactivity secondary to bladder outlet obstruction resulting from prostatic enlargement or proximal urethral smooth muscle hyperreactivity.
  • Approved therapies for these conditions include treatment with 5 ⁇ - reductase inhibitors, such as finaste ⁇ de, (US Patents 4,377,584 and 4,760,071) which shrink the prostate; and ⁇ -adrenergic receptor blockers such as terazosin (US Patent 4,026,894) or doxazosin (US Patent 4,188,390) which relax smooth muscle.
  • 5 ⁇ - reductase inhibitors such as finaste ⁇ de, (US Patents 4,377,584 and 4,760,071) which shrink the prostate
  • ⁇ -adrenergic receptor blockers such as terazosin (US Patent 4,026,894) or doxazosin (US Patent 4,188,390) which relax smooth muscle.
  • Combinations of 5 ⁇ -reductase inhibitors with ⁇ -adrenergic blockers have been desc ⁇ bed for use m the treatment of benign prostatic hyperplasia (US Patent 5,753,641). Bladder outlet obstruction may result in detrusor muscle hyperreactivity which may manifest itself as urge/urge incontinence. Musca ⁇ nic receptor antagonists, including those with relative specificity for the M3 receptor- subtype can be used to treat urge/urge incontinence.
  • compositions comprising a musca ⁇ nic receptor antagonist and at least one agent of an approved therapeutic class for the treatment of benign prostatic hypertrophy (BPH)
  • BPH benign prostatic hypertrophy
  • This invention is concerned with methods of treatment of Lower U ⁇ nary Tract Symptoms (LUTS) and pharmaceutical compositions comp ⁇ sing a musca ⁇ nic receptor antagonist and at least one other active ingredient selected from a 5 ⁇ -reductase inhibitor and an ⁇ -adrenergic receptor blocker.
  • LUTS Lower U ⁇ nary Tract Symptoms
  • One embodiment of this invention is a pharmaceutical composition comp ⁇ sing an effective amount of a combination of (a) a musca ⁇ nic receptor antagonist; and at least one other active ingredient selected from (b) a 5 ⁇ -reductase inhibitor, and (c) an ⁇ -adrenergic receptor blocker, in combination with a pharmaceutically acceptable earner.
  • musca ⁇ nic receptor antagonists useful in the compositions of this invention include but are not limited to tolterod e, oxybutinm, da ⁇ fenacm and a compound of structure I and related compounds disclosed and claimed in WO98/05641 (US Patent Application Se ⁇ al No. 08/903768. filed July 30, 1997) and pharmaceutically acceptable salts thereof.
  • 5 -reductase inhibitor compounds useful in the compositions and methods of the present invention are those of structural formula II (US Patent 4,377,584).
  • R is selected from
  • Ci-io alkyl unsubstituted or substituted with one to three halogen substituents
  • R is selected from
  • R is t- butyl to provide the compound, fmaste ⁇ de
  • R is 2,5-b ⁇ s(t ⁇ fluoromethyl)phenyl, to provide the compound, dutaste ⁇ de (US Patent 5,565,467).
  • halo or halogen is meant to include fluoro, chloro, bromo and lodo.
  • Ci -io alkyl is meant to include both straight-and branched- chain alkyl groups of one to ten carbon atoms in length, not limited to: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the isomers thereof such as isopropyl, isobutyl, secbutyl, t-butyl, isopentyl, isohexyl, etc.
  • the preferred 5 ⁇ -reductase inhibitor of the above type is fmaste ⁇ de (shown below) disclosed in US Patent 4,760,071, which is incorporated by reference herein in its entirety
  • inhibitors of 5 ⁇ -reductase type 2 useful in the methods of the present invention include ep ⁇ ste ⁇ de (US Patent 5,017,568), turoste ⁇ de (US Patent 5,155,107) and dutaste ⁇ de (US Patent 5,565,467) shown below All three US patents are incorporated by reference herein in their entirety
  • the ⁇ -adrenergic receptor blockers useful in the pharmaceutical compositions of this invention include but are not limited to terazosin (US Patent 4,026,894), doxazosin (US Patent 4,188,390), prazosin (US Patent 3,511,836), bunazosin (US Patent 3,920,636), lndoramin (US Patent 3,527,761), alfuzosin (US Patent 4,315,007), abanoquil (US Patent 4.686,228), naftopidil (US Patent 3,997.666), phentolamine, tamsulosin (US Patent 4,703,063), trazodone, dapiprazole, phenoxybenzamine, idazoxan (US Patent 4,818,764), efaroxan (US Patent 4,411,908) and yohimbine, and pharmaceutically acceptable salts thereof
  • Preferred ⁇ -blockers include but are not limited to terazosin (US Patent 4,02
  • each active ingredient is present m an amount that would be present in a formulation comp ⁇ sing it as a sole active ingredient
  • the musca ⁇ nic receptor antagonist is present in an amount ranging from about 0 2 mg to about 20 mg, preferably about 2 mg per dose
  • the 5 ⁇ -reductase inhibitor is present in an amount ranging from about 2 mg to about 20 mg, preferably about 5 mg per dose
  • the ⁇ -adrenergic receptor blocker is present in an amount ranging from about 1 mg to about 25 mg, and preferably about 10 mg per dose
  • compositions containing the active ingredients may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavo ⁇ ng agents, colo ⁇ ng agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, corn starch or alginic acid, binding agents, for
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example peanut oil, liquid paraffin, or olive oil
  • Aqueous suspensions contain the active mate ⁇ al in admixture with excipients suitable for the manufacture of aqueous suspensions
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvmyl-pyrrohdone, gum tragacanth and gum acacia
  • dispersing or wetting agents may be a naturally-occur ⁇ ng phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters de ⁇ ved from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters de ⁇ ved from fatty acids and hexitol anh
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set forth above, and flavo ⁇ ng agents may be added to provide a palatable oral preparation
  • a thickening agent for example, beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set forth above, and flavo ⁇ ng agents may be added to provide a palatable oral preparation
  • an anti-oxidant such as ascorbic acid
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above Additional excipients, for example, sweetening, flavo ⁇ ng and colo ⁇ ng agents, may also be present
  • compositions of the invention may also be in the form of an oil-in-water emulsions
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these Suitable emulsifying agents may be naturally-occur ⁇ ng phosphatides, for example, soybean, lecithin, and esters or partial esters de ⁇ ved from fatty acids and hexitol anhyd ⁇ des, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxy-ethylene sorbitan monooleate
  • the emulsions may also contain sweetening and flavou ⁇ ng agents
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose Such formulations may also contain a demulcent, a preservative and flavo ⁇ ng and colo ⁇ ng agents
  • the pharmaceutical compositions may be in the form of a ste ⁇ le injectable aqueous or oleagenous suspension This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above
  • the ste ⁇ le injectable preparation may also be a ste ⁇ le injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butaned ⁇ ol
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chlo ⁇ de solution Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used
  • compositions can be prepared by mixing the drug with a suitable non-ir ⁇ tating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug
  • suitable non-ir ⁇ tating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug
  • Such mate ⁇ als are cocoa butter and polyethylene glycols
  • Another embodiment of this invention is a method of treating Lower U ⁇ nary Tract Symptoms (LUTS) comp ⁇ sing the administration of an effective amount of a composition comp ⁇ smg (a) a musca ⁇ nic receptor antagonist and at least one member selected from the group consisting of (b) a 5 ⁇ -reductase inhibitor and (c) an ⁇ -adrenergic receptor blocker to a patient in need of such treatment
  • LUTS Lower U ⁇ nary Tract Symptoms
  • an "effective amount” as used herein is that amount of the composition that will elicit the biological or medical response being sought
  • the daily dose of each of the active agents employed in the method of treatment of this invention is similar to the doses desc ⁇ bed for use in the pharmaceutical composition. It will be understood, however, that the specific dose level for any particular patient may depend upon a va ⁇ ety of factors including the age, body weight, general health, diet, time of administration, route of administration, rate of excretion, drug combination and the seventy of the particular disease undergoing therapy
  • the two or three active agents being administered in the method of treatment of this invention can be administered together combined in a single dosage form or they can be administered separately, essentially concurrently, each in its own dosage form but as part of the same therapeutic treatment program or regimen, and it is contemplated that separate administration of each compound, at different times and by different routes, will sometimes be recommended Thus, the two or three components need not necessa ⁇ ly be administered at the same time.
  • administration is timed so that the peak pharmacokmetic effect of one component coincides with the peak pharmacokinetic effect for the other component(s).
  • EXAMPLE 1 Tablet Preparation Tablets containing 2 mg. of muscannic receptor antagonist and 5 mg. of 5 ⁇ -reductase inhibitor are prepared as illustrated below.
  • Tablets are prepared from the above composition by substantially the same procedure as desc ⁇ bed m Example 1

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne le traitement d'un état médical, touchant les hommes, connu sous le nom de symptômes des voies urinaires basses par l'administration d'un antagoniste du récepteur muscarinique en association avec un inhibiteur de 5α-réductase au moins et un agent de blocage du récepteur α-adrénergique.
PCT/US2000/025534 1999-09-22 2000-09-18 Traitement des symptomes des voies urinaires basses, et compositions pharmaceutiques a utiliser dans le cadre dudit traitement WO2001021167A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU77037/00A AU7703700A (en) 1999-09-22 2000-09-18 Treatment of lower urinary tract symptoms and pharmaceutical compositions for use therein

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15535799P 1999-09-22 1999-09-22
US60/155,357 1999-09-22

Publications (2)

Publication Number Publication Date
WO2001021167A1 true WO2001021167A1 (fr) 2001-03-29
WO2001021167A8 WO2001021167A8 (fr) 2001-09-07

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AU (1) AU7703700A (fr)
WO (1) WO2001021167A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1123705A1 (fr) * 2000-02-09 2001-08-16 Pfizer Products Inc. Combinaisons pharmaceutiques pour le traitement de troubles fonctionnels de l' uretère inférieur
WO2003026564A2 (fr) * 2001-09-27 2003-04-03 Pharmacia Ab Composition pharmaceutique
WO2003090753A1 (fr) * 2002-04-24 2003-11-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Combinaison pharmaceutique pour le traitement de l'hyperplasie prostatique benigne ou pour la prevention a long terme de la retention urinaire aigue
WO2005092342A1 (fr) * 2004-03-22 2005-10-06 Ranbaxy Laboratories Limited Therapie de combinaison pour symptomes du tractus urinaire inferieur
WO2008120967A1 (fr) * 2007-04-02 2008-10-09 Espinosa Abdala Leopoldo De Jesus COMPOSITIONS PHARMACEUTIQUES SYNERGIQUES COMPRENANT UNE COMBINAISON D'UN INHIBITEUR DE L'ENZYME 5 α-RÉDUCTASE ET D'UN ANTAGONISTE DES RÉCEPTEURS 1 α- ADRÉNERGIQUES
EP2363397A1 (fr) * 2008-11-07 2011-09-07 Dainippon Sumitomo Pharma Co., Ltd. Nouvel agent thérapeutique utile pour un symptôme du tractus urinaire inférieur

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995031190A1 (fr) * 1994-05-18 1995-11-23 Hisamitsu Pharmaceutical Co., Inc. Preparation administrable par voie percutanee pour le traitement des troubles de la miction

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995031190A1 (fr) * 1994-05-18 1995-11-23 Hisamitsu Pharmaceutical Co., Inc. Preparation administrable par voie percutanee pour le traitement des troubles de la miction

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] (COLUMBUS, OHIO, USA); DE MEY C. ET AL.: "A double-blind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and nocturnal orthostatic stress testing", XP002935741, accession no. STN Database accession no. 1998:542045 *
DATABASE CAPLUS [online] (COLUMBUS, OHIO, USA); DEBRUYNE F. ET AL.: "Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia", XP002935740, accession no. STN Database accession no. 1998:637676 *
DATABASE CAPLUS [online] (COLUMBUS, OHIO, USA); NAKAMURA K. ET AL.: "Percutaneously administrable preparation for treating urination disorder", XP002935739, accession no. STN Database accession no. 1996:73296 *
EUR. UROL., vol. 33, no. 5, 1998, pages 481 - 488 *
EUR. UROL., vol. 34, no. 3, 1998, pages 169 - 175 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1123705A1 (fr) * 2000-02-09 2001-08-16 Pfizer Products Inc. Combinaisons pharmaceutiques pour le traitement de troubles fonctionnels de l' uretère inférieur
EP2266571A1 (fr) * 2000-02-09 2010-12-29 Novartis International Pharmaceutical Ltd. Combinaisons pharmaceutiques pour le traitement de troubles fonctionnels de l' uretère inférieur
US7138405B2 (en) 2000-02-09 2006-11-21 Novartis International Pharmaceutical Ltd Pharmaceutical combinations
WO2003026564A3 (fr) * 2001-09-27 2003-12-11 Pharmacia Ab Composition pharmaceutique
WO2003026564A2 (fr) * 2001-09-27 2003-04-03 Pharmacia Ab Composition pharmaceutique
WO2003090753A1 (fr) * 2002-04-24 2003-11-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Combinaison pharmaceutique pour le traitement de l'hyperplasie prostatique benigne ou pour la prevention a long terme de la retention urinaire aigue
EP1743656A3 (fr) * 2002-04-24 2007-03-07 Boehringer Ingelheim Pharma GmbH & Co. KG Combinaison pharmaceutique pour le traitement de l'hyperplasie prostatique benigne ou pour la prévention à long terme de la rétention urinaire aigue
EA008377B1 (ru) * 2002-04-24 2007-04-27 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Фармацевтическая комбинация для лечения доброкачественной гиперплазии простаты или для долговременной профилактики острой ишурии
WO2005092342A1 (fr) * 2004-03-22 2005-10-06 Ranbaxy Laboratories Limited Therapie de combinaison pour symptomes du tractus urinaire inferieur
WO2005092341A1 (fr) * 2004-03-22 2005-10-06 Ranbaxy Laboratories Limited Therapie combinee destinee a reduire les symptomes des voies urinaires
WO2008120967A1 (fr) * 2007-04-02 2008-10-09 Espinosa Abdala Leopoldo De Jesus COMPOSITIONS PHARMACEUTIQUES SYNERGIQUES COMPRENANT UNE COMBINAISON D'UN INHIBITEUR DE L'ENZYME 5 α-RÉDUCTASE ET D'UN ANTAGONISTE DES RÉCEPTEURS 1 α- ADRÉNERGIQUES
EP2363397A1 (fr) * 2008-11-07 2011-09-07 Dainippon Sumitomo Pharma Co., Ltd. Nouvel agent thérapeutique utile pour un symptôme du tractus urinaire inférieur
EP2363397A4 (fr) * 2008-11-07 2012-07-11 Dainippon Sumitomo Pharma Co Nouvel agent thérapeutique utile pour un symptôme du tractus urinaire inférieur

Also Published As

Publication number Publication date
WO2001021167A8 (fr) 2001-09-07
AU7703700A (en) 2001-04-24

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